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WO2002028865A2 - Composés chimiques - Google Patents

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Publication number
WO2002028865A2
WO2002028865A2 PCT/US2001/042175 US0142175W WO0228865A2 WO 2002028865 A2 WO2002028865 A2 WO 2002028865A2 US 0142175 W US0142175 W US 0142175W WO 0228865 A2 WO0228865 A2 WO 0228865A2
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Prior art keywords
alkyl
group
compound
hydrogen
aryl
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PCT/US2001/042175
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English (en)
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WO2002028865A3 (fr
Inventor
Mark W. Orme
Jason Scott Sawyer
Alain Claude-Marie Daugan
Romain Luc Marie Gosimini
Lisa M. Schultze
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Lilly Icos Llc
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Priority to DE60121461T priority Critical patent/DE60121461T2/de
Priority to JP2002532448A priority patent/JP4246488B2/ja
Priority to US10/363,528 priority patent/US6858620B2/en
Priority to MXPA03002911A priority patent/MXPA03002911A/es
Priority to AU2002213421A priority patent/AU2002213421A1/en
Priority to CA002423312A priority patent/CA2423312A1/fr
Priority to EP01981804A priority patent/EP1335923B1/fr
Publication of WO2002028865A2 publication Critical patent/WO2002028865A2/fr
Publication of WO2002028865A3 publication Critical patent/WO2002028865A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/06—Antiabortive agents; Labour repressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
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    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
    • C07D513/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D515/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D515/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
    • C07D515/14—Ortho-condensed systems

Definitions

  • This invention relates to a series of compounds, to methods of preparing the compounds, to pharmaceutical compositions containing the compounds, and to their use as therapeutic agents.
  • the invention relates to compounds that are potent and selective inhibitors of cyclic guanosine 3 ' , 5 ' -monophosphate specific phosphodi- esterase (cGMP-specific PDE) , in particular PDE5, and have utility in a variety of therapeutic areas wherein such inhibition is considered beneficial, including the treatment of cardiovascular disorders and erectile dysfunction.
  • cGMP-specific PDE cyclic guanosine 3 ' , 5 ' -monophosphate specific phosphodi- esterase
  • the present invention provides compounds of formula (I)
  • R 1 is selected from the group consisting of optionally substituted aryl, optionally substituted heteroaryl, an optionally substituted C 3 - 8 cycloalkyl ring, an optionally substituted C 3 . 8 heterocycloalkyl ring, an optionally substituted bicyclic ring
  • R 2 and R 4 are selected from the group consisting of hydrogen, Ci.galkyl, aryl, heteroaryl, arylC h alk ! , C x _ 3 alkylenearyl , Ci_ 3 alkyl- eneHet, C 3 _ 8 cycloalkyl, and C 3 . 8 heterocycloalkyl;
  • R 3 is selected from the group consisting of hydrogen, Ci.galkyl, C 3 . 8 cycloalkyl, C 3 . 8 heterocyclo- alkyl, C 2 . 5 alkenyl, C x . 3 alkylenearyl , arylC x .
  • R b is selected from the group consisting of hydrogen, C x _ 6 alkyl, aryl, arylC x . 3 alkyl , C x . 3 alkyl- enearyl , heteroaryl, heteroarylC ⁇ alkyl, and C x _ 3 - alkyleneheteroaryl ;
  • R c is selected from the group consisting of hydrogen, C x _ 6 alkyl , C 3 _ 8 cycloalkyl , C x _ 3 alkyleneN (R) 2 , aryl, arylC x _ 3 alkyl , C x _ 3 alkylenearyl , and heteroaryl; R d is selected from the group consisting of hydrogen, C x .
  • R b and R d are taken together to form a 5- or 6-membered ring, optionally containing at least one heteroatom;
  • R e is null or is selected from the group consisting of hydrogen, C x _ 6 alkyl, aryl, heteroaryl, arylC x _ 3 alkyl, heteroarylC x _ 3 alkyl , C x _ 3 alkylenearyl, and C x _ 3 alkyleneheteroaryl ;
  • Q is 0, S, or NR b ;
  • B is 0, S, or NR e ;
  • C is 0, S, or NR b ;
  • D is CR b or N
  • E is CR b , C(R a ) 2 , or NR e ;
  • alkyl includes straight chained and branched hydrocarbon groups containing the indicated number of carbon atoms, typically methyl, ethyl, and straight chain and branched propyl and butyl groups.
  • the hydrocarbon group can contain up to 16 carbon atoms.
  • alkyl includes "bridged alkyl/" i.e., a C 6 -C 16 bicyclic or polycyclic hydrocarbon group, for example, norbornyl, adamantyl, bicyclo [2.2.2] octyl, bicyclo [2.2. l]heptyl, bicyclo [3.2.1] octyl , or deca- hydronaphthyl .
  • cycloalkyl is defined as a cyclic C 3 -C 8 hydrocarbon group, e.g., cyclopropyl, cyclobutyl, cyclohexyl, and cyclopentyl .
  • alkenyl and alkynyl are defined identically as “alkyl,” except for containing a carbon-carbon double bond or carbon-carbon triple bond, respectively.
  • Cycloalkenyl is defined similarly to cycloalkyl, except a carbon-carbon double bond is present in the ring.
  • alkylene refers to an alkyl group having a substituent.
  • C ⁇ _ 3 alkylenearyl refers to an alkyl group containing one to three carbon atoms, and substituted with an aryl group.
  • alkenylene as used herein is similarly defined, and contains the indicated number of carbon atoms and a carbon-carbon double bond, and includes straight chained and branched alkenylene groups, like ethyenylene .
  • halo or “halogen” is defined herein to include fluorine, bromine, chlorine, and iodine .
  • haloalkyl is defined herein as an alkyl group substituted with one or more halo substituents, either fluoro, chloro, bromo, iodo, or combinations thereof.
  • halocycloalkyl is defined as a cycloalkyl group having one or more halo substituents.
  • aryl alone or in combination, is defined herein as a monocyclic or polycyclic aromatic group, preferably a monocyclic or bicyclic aromatic group, e.g., phenyl or naphthyl .
  • an "aryl” group can be unsub- stituted or substituted, for example, with one or more, and in particular one to three, halo, alkyl, hydroxyalkyl, alkoxy, alkoxyalkyl, haloalkyl, nitro, amino, alkylamino, acylamino, alkylthio, alkylsul- finyl, and alkylsulfonyl .
  • aryl groups include phenyl, naphthyl, tetrahydronaphthyl , 2- chlorophenyl , 3-chlorophenyl, 4-chlorophenyl, 2- methylphenyl, 4-methoxyphenyl, 3-trifluoromethyl- phenyl , 4-nitrophenyl, and the like.
  • arylCi_ 3 alkyl and “heteroarylC ⁇ _ 3 alkyl” are defined as an aryl or heteroaryl group having a C x . 3 alkyl substituent .
  • heteroaryl is defined herein as a monocyclic or bicyclic ring system containing one or two aromatic rings and containing at least one nitrogen, oxygen, or sulfur atom in an aromatic ring, and which can be unsubstituted or substituted, for example, with one or more, and in particular one to three, substituents, like halo, alkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, haloalkyl, nitro, amino, alkylamino, acylamino, alkylthio, alkylsul- finyl, and alkylsulfonyl .
  • heteroaryl groups include thienyl, furyl , pyridyl, oxazolyl, quinolyl, isoquinolyl, indolyl , triazolyl, isothia- zolyl, isoxazolyl, imidizolyl, benzothiazolyl , pyra- zinyl, pyrimidinyl, thiazolyl, and thiadiazolyl .
  • Het is defined as monocyclic, bicyclic, and tricyclic groups containing one or more heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur.
  • Nonlimiting examples of Het groups include 1,3- dioxolane, 2-pyrazoline, pyrazolidine, pyrrolidine, piperazine, a pyrroline, 2H-pyran, 4H-pyran, morph- oline, thiopholine, piperidine, 1, 4-dithiane, and 1,4-dioxane.
  • hydroxy is defined as -OH.
  • alkoxy is defined as -OR, wherein R is alkyl.
  • alkoxyalkyl is defined as an alkyl group wherein a hydrogen has been replaced by an alkoxy group.
  • (alkylthio) alkyl is defined similarly as alkoxyalkyl, except a sulfur atom, rather than an oxygen atom, is present.
  • hydroxyalkyl is defined as a hydroxy group appended to an alkyl group.
  • amino is defined as -NH 2
  • alkylamino is defined as -NR 2 , wherein at least one R is alkyl and the second R is alkyl or hydrogen.
  • alkylthio is defined as -SR, wherein R is alkyl .
  • alkylsulfinyl is defined as R-S0 2 , wherein R is alkyl.
  • alkylsulfonyl is defined as
  • R-S0 3 wherein R is alkyl.
  • nitro is defined as -N0 2 .
  • trifluoromethyl is defined as -CF 3 .
  • trifluoromethoxy is defined as
  • spiro refers to a group having two carbon atoms directly bonded to the carbon atom to which R 1 is attached.
  • cyano is defined as -CN.
  • R 1 is represented by
  • bicyclic ring can represent, for example, naphthalene or indene, or a hetero- cycle, such as benzoxazole, benzothiazole, benzi- soxazole, benzimidazole, quinoline, indole, benzothiophene, or benzofuran, or
  • q is an integer 1 or 2
  • G independently, is C(R a ) 2 , O, S, or NR a .
  • the bicyclic ring comprising the R 1 substituent typically is attached to the rest of the molecule by a phenyl ring carbon atom.
  • R 1 is represented by an optionally substituted bicyclic ring
  • R 1 substituents include
  • nonlimit- ing examples of substituents for the bicyclic ring include halogen (e.g., chlorine), C x _ 3 alkyl (e.g., methyl, ethyl, or i-propyl) , OR a (e.g., methoxy, ethoxy, or hydroxy) , C0 2 R a , halomethyl or halomethoxy (e.g., trifluoromethyl or trifluoromethoxy) , cyano, nitro, and NR a R b .
  • halogen e.g., chlorine
  • C x _ 3 alkyl e.g., methyl, ethyl, or i-propyl
  • OR a e.g., methoxy, ethoxy, or hydroxy
  • C0 2 R a e.g., halomethyl or halomethoxy (e.g., trifluoromethyl or trifluoromethoxy)
  • R 1 is optionally substituted and selected from the group consisting of C x _ 4 alkyleneQR a , C x _ 4 alkyleneQC x _ 4 alkyl- eneQR a , C 3 _ 8 cycloalkyl , C 3 . 8 cycloalkenyl, C x . 6 alkyl,
  • R 1 is represented by
  • a preferred Q is oxygen.
  • R 1 substituents include
  • R a substituents include hydrogen, C ⁇ . 6 alkyl, and benzyl .
  • R 3 is selected from the group consisting of C x _ 4 alkylene- heteroaryl, wherein the heteroaryl group is selected from the group consisting of benzimidazole, a tri- azole, and imidazole; C x _ 4 alkyleneHet , wherein Het is selected from the group consisting of piperazine, morpholine, pyrrolidine, pyrrolidone, tetrahydro- furan, piperidine,
  • R 2 and R 4 independently, are hydrogen, C x . 6 alkyl, aryl, or heteroaryl .
  • R° is selected from the group consisting of halo, methyl, trifluoromethyl, and trifluoromethyl ;
  • R 1 is selected from the group consisting of
  • R 2 and R 4 are selected from the group consisting of hydrogen and C x . 6 alkyl;
  • -X-Z-Y- is selected from the group consisting of
  • R d is hydrogen, benzyl, or C x . 6 alkyl .
  • R d is hydrogen, benzyl, or C x . 6 alkyl .
  • Compounds of formula (I) can contain one or more asymmetric center, and, therefore, can exist as stereoisomers.
  • the present invention includes both mixtures and separate individual stereoisomers of the compounds of formula (I) .
  • Compounds of formula (I) also can exist in tautomeric forms, and the invention includes both mixtures and separate individual tautomers thereof .
  • Pharmaceutically acceptable salts of the compounds of formula (I) can be acid addition salts formed with pharmaceutically acceptable acids.
  • suitable salts include, but are not limited to, the hydrochloride, hydrobromide , sulfate, bisulfate, phosphate, hydrogen phosphate, acetate, benzoate, succinate, fumarate, maleate, lac- tate, citrate, tartrate, gluconate, methanesul- fonate, benzenesulfonate, and p-toluenesulfonate salts.
  • the compounds of the formula (I) also can provide pharmaceutically acceptable metal salts, in particular alkali metal salts and alkaline earth metal salts, with bases. Examples include the so- dium, potassium, magnesium, and calcium salts.
  • Compounds of the present invention are potent and selective inhibitors of cGMP-specific PDE5.
  • compounds of formula (I) are of interest for use in therapy, specifically for the treat- ment of a variety of conditions where selective inhibition of PDE5 is considered to be beneficial .
  • Phosphodiesterases catalyze the hydrolysis of cyclic nucleotides, such as cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) .
  • cyclic nucleotides such as cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) .
  • the PDEs have been classified into at least seven isoenzyme families and are present in many tissues (J.A. Beavo, Physiol . Rev. , 75, p. 725 (1995) ) .
  • PDE5 inhibition is a particularly attractive target .
  • a potent and selective inhibitor of PDE5 provides vasodilating, relaxing, and diuretic effects, all of which are beneficial in the treat- ment of various disease states. Research in this area has led to several classes of inhibitors based on the cGMP basic structure (E. Sybertz et
  • the biochemical, physiological, and clini- cal effects of PDE5 inhibitors therefore suggest their utility in a variety of disease states in which modulation of smooth muscle, renal, hemostat- ic, inflammatory, and/or endocrine function is desirable.
  • the compounds of formula (I) therefore, have utility in the treatment of a number of disorders, including stable, unstable, and variant (Prinzmetal) angina, hypertension, pulmonary hypertension, congestive heart failure, acute respiratory distress syndrome, acute and chronic renal failure, atherosclerosis, conditions of reduced blood vessel patency (e.g., postpercutaneous transluminal coronary or carotid angioplasty, or post-bypass surgery graft 'Stenosis) , peripheral vascular disease, vascular disorders, such as Raynaud's disease, thrombo- cythemia, inflammatory diseases, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma, osteoporosis, preterm labor, benign pros- t
  • Impotence can be defined as a lack of power, in the male, to copulate, and can involve an inability to achieve penile erection or ejaculation, or both.
  • the incidence of erectile dysfunction increases with age, with about 50% of men over the age of 40 suffering from some degree of erectile dysfunction.
  • Female arousal disorders are defined as a recurrent inability to attain or maintain an adequate lubrication/- swelling response of sexual excitement until completion of sexual activity.
  • the arousal response consists of vasocongestion in the pelvis, vaginal lu- brication, and expansion and swelling of external genitalia.
  • compounds of formula (I) are useful in the treatment of male erectile dysfunction and female arousal disor- der.
  • the present invention concerns the use of compounds of formula (I) , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing either entity, for the manufacture of a medicament for the curative or prophylactic treatment of erectile dysfunction in a male animal and arousal disorder in a female animal, including humans .
  • treatment includes preventing, lowering, stopping, or reversing the progression or severity of the condition or symptoms being treated.
  • treatment includes both medical therapeutic and/or prophylactic administration, as appropriate. It also is understood that "a compound of formula (I) , " or a physiologically acceptable salt or solvate thereof , can be administered as the neat compound, or as a pharmaceutical composition con- taining either entity.
  • the compounds of the invention are envisioned primarily for the treatment of sexual dysfunction in humans, such as male erectile dysfunction and female arousal disorder, they also can be used for the treatment of other disease states.
  • a further aspect of the present invention is providing a compound of formula (I) for use in the treatment of stable, unstable, and variant (Prinzmetal) angina, hypertension, pulmonary hypertension, chronic obstructive pulmonary disease, congestive heart failure, acute respiratory distress syndrome, acute and chronic renal failure, atherosclerosis, conditions of reduced blood vessel patency (e.g., post-PTCA or post-bypass graft stenosis), peripheral vascular disease, vascular disorders such as Raynaud's disease, thrombocythernia, inflammatory diseases, prophylaxis of myocardial infarction, prophylaxis of stroke, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glau- coma, osteoporosis, preterm labor, benign prostatic hypertrophy, male and female erectile dysfunction, or diseases characterized by disorders of gut motil- ity (e.g. , IBS) .
  • IBS intestinal motil-
  • the present invention provides a method of treating the above-noted conditions and disorders in a human or nonhuman animal body which comprises administering to said body a therapeutically effective amount of a compound of formula (I) .
  • Compounds of the invention can be administered by any suitable route, for example by oral, buccal, inhalation, sublingual, rectal, vaginal, transurethral, nasal, topical, percutaneous, i.e., transdermal, or parenteral (including intravenous, intramuscular, subcutaneous, and intracoronary) administration.
  • Parenteral administration can be accomplished using a needle and syringe, or using a high pressure technique, like POWDERJECTTM.
  • Oral administration of a compound of the invention is the preferred route. Oral administration is the most convenient and avoids the disadvantages associated with other routes of administra- tion.
  • the drug can be administered parenterally, e.g., sublingually or buccally.
  • compositions suitable for use in the present invention include those wherein the active ingredient is administered in an effective amount to achieve its intended purpose. More specifically, a "therapeutically effective amount” means an amount effective to prevent development of, or to alleviate the existing symptoms- of, the subject being treated. Determination of the effective amounts is well within the capabilities- ity of those skilled in the art, especially in light of the detailed disclosure provided herein.
  • a “therapeutically effective dose” refers to that amount of the compound that results in achieving the desired effect. Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD 50 (the dose lethal to 50% of the population) and the ED S0 (the dose therapeutically effective in 50% of the population) . The dose ratio between toxic and therapeutic effects is the therapeutic index, which is expressed as the ratio between LD 50 and ED 50 . Compounds which exhibit high therapeutic indices are preferred. The data obtained from such data can be used in formulating a dosage range for use in humans . The dosage of such compounds preferably lies within a range of circulating concentrations that include the ED 50 with little or no toxic- ity. The dosage can vary within this range depending upon the dosage form employed, and the route of administration utilized.
  • the exact formulation, route of administration, and dosage can be chosen by the individual physician in view of the patient's condition. Dosage amount and interval can be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the therapeutic effects.
  • oral dosages of a compound of formula (I) generally are about 0.5 to about 1000 mg daily for an average adult patient (70 kg) .
  • individual tablets or capsules contain 0.2 to 500 mg of active compound, in a suitable pharmaceutically acceptable vehicle or carrier, for admin- istration in single or multiple doses, once or several times per day.
  • Dosages for intravenous, buccal, or sublingual administration typically are 0.1 to 500 mg per single dose as required.
  • the physician determines the actual dosing regimen which is most suitable for an individual patient, and the dosage varies with the age, weight, and response of the particular patient.
  • the above dosages are exemplary of the average case, but there can be individual instances in which higher or lower dosages are merited, and such are within the scope of this invention.
  • a compound of the formula (I) can be administered alone, but generally is administered in admixture with a pharmaceutical car- rier selected with regard to the intended route of administration and standard pharmaceutical practice.
  • Pharmaceutical compositions for use in accordance with the present invention thus can be formulated in a conventional manner using one or more physiologi- cally acceptable carriers comprising excipients and auxiliaries that facilitate processing of compounds of formula (I) into preparations which can be used pharmaceutically.
  • These pharmaceutical compositions can be manufactured in a conventional manner, e.g., by conventional mixing, dissolving, granulating, dragee- making, levigating, emulsifying, encapsulating, en- trapping, or lyophilizing processes. Proper formulation is dependent upon the route of administration chosen.
  • the composition typically is in the form of a tablet, capsule, powder, solution, or elixir.
  • the composition can additionally contain a solid carrier, such as a gelatin or an adjuvant.
  • a solid carrier such as a gelatin or an adjuvant.
  • the tablet, capsule, and powder contain about 5 to about 95% compound of the present invention, and preferably from about 25 to about 90% compound of the present invention.
  • a liquid carrier such as water, petroleum, or oils of animal or plant origin can be added.
  • the liquid form of the compo- sition can further contain physiological saline solution, dextrose or other, saccharide solutions, or glycols.
  • the composition contains about 0.5 to about 90% by weight of a compound of the present invention, and preferably about 1 to about 50% of a compound of the present invention.
  • compositions When a therapeutically effective amount of a compound of the present invention is administered by intravenous, cutaneous, or subcutaneous injec- tion, the composition is in the form of a pyrogen- free, parenterally acceptable aqueous solution.
  • parenterally acceptable solutions having due regard to pH, isotonicity, stabil- ity, and the like, is within the skill in the art.
  • a preferred composition for intravenous, cutaneous, or subcutaneous injection typically contains, in addition to a compound of the present invention, an isotonic vehicle.
  • the compounds can be formulated readily by combining a compound of formula (I) with pharmaceutically acceptable carriers well known in the art.
  • Such carriers enable the present compounds to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated.
  • Pharmaceutical preparations for oral use can be obtained by adding a compound of formula (I) with a solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • Suitable excipients include, for example, fillers and cellulose preparations. If desired, disintegrating agents can be added.
  • compounds of the present invention are conveniently delivered in the form of an aerosol spray presenta- tion from pressurized packs or a nebulizer, with the use of a suitable propellant.
  • the dosage unit can be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of, e.g., gelatin, for use in an inhaler or insufflator can be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
  • the compounds can be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • Formulations for injection can be presented in unit dosage form, e.g., in ampules or in multidose containers, with an added preservative.
  • the compositions can take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formula- tory agents such as suspending, stabilizing, and/or dispersing agents.
  • compositions for parenteral administration include aqueous solutions of the active compounds in water-soluble form.
  • suspensions of the active compounds can be prepared as appropriate oily injection suspensions.
  • Suitable lipophilic solvents or vehicles include fatty oils or synthetic fatty acid esters.
  • Aqueous injection suspensions can contain substances which increase the viscosity of the suspension.
  • the suspension also can contain suitable stabilizers or agents that increase the solubility of the compounds and allow for the preparation of highly concentrated solutions.
  • a present composition can be in powder form for con- stitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • Compounds of the present invention also can be formulated in rectal compositions, such as suppositories or retention enemas, e.g., containing conventional suppository bases.
  • the compounds also can be formulated as a depot preparation.
  • Such long-acting formulations can be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds can be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • a compound of formula (I) can be administered orally, buccally, or sublin- gually in the form of tablets containing excipients, such as starch or lactose, or in capsules or ovules, either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents.
  • excipients such as starch or lactose
  • capsules or ovules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents.
  • Such liquid preparations can be prepared with pharmaceutically acceptable additives, such as suspending agents.
  • a compound also can be injected parenterally, for example, intravenously, intramuscularly, subcutaneously, or intracoronarily.
  • parenteral administration the compound is best used in the form of a sterile aqueous solution which can contain other substances, for example, salts, or monosaccharides, such as mannitol or glucose, to make the solution isotonic with blood.
  • a compound of formula (I) or a nontoxic salt thereof is administered as a suitably acceptable formulation in accordance with normal veterinary practice.
  • the veterinarian can readily determine the dosing regimen and route of administration that is most appropriate for a par- ticular animal.
  • the invention provides in a further aspect a pharmaceutical composition comprising a compound of the formula (I) , together with a pharmaceutically acceptable diluent or carrier therefor.
  • a process of preparing a pharmaceutical composition comprising a compound of formula (I) , which process comprises mixing a compound of formula (I) , together with a pharmaceutically acceptable diluent or car- rier therefor.
  • the invention includes a pharmaceutical composition for the curative or prophylactic treatment of erectile dysfunction in a male animal, or arousal disorder in a female animal, including humans, comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier.
  • a compound of structural formula (I) is prepared similarly by reacting a tryptophan ester, or a tryptophan ester substituted with suitable R° substituents, with a suitable aldehyde to provide the desired R 1 substituent.
  • the resulting product then is hydrolyzed to the carboxylic acid, and cyclized by reaction with a suitable cyclizing agent like phosgene, thiocarbonyl diimidazole, or thio- phosgene, for example, to provide a compound of structural formula (I) .
  • protecting compounds and protect- ing groups like benzyl chloroformate and trichloro- ethyl chloroformate, which are well known to persons skilled in the art, can be used.
  • protecting groups are disclosed, for example, in T.W. Greene et al . "Protective Groups in Organic Synthesis, Third Edition," John Wiley and Sons, Inc., NY, NY (1999).
  • the structure of a compound of structural formula (I) can be varied by using an appropriate aldehyde to change the identity of R 1 , or by using a halo or alkyl phenyl-substituted tryptophan ester.
  • Compounds of formula (I) can be converted to other compounds of formula (I) .
  • a compound contains a substituted aromatic ring
  • suitable interconversions include, but are not limited to, 0R b to hydroxy by suitable means (e.g., using an agent such as SnCl 2 or a palladium catalyst, such as palladium-on-carbon, or amino to substituted amino, such as alkylamine, using standard acylating or sulfonylating conditions.
  • Compounds of formula (I) can be prepared by the method above as individual stereoisomers from the appropriate stereoisomer of formula (III) or as a racemic mixture from the appropriate racemic compound of formula (III) .
  • Individual stereoisomers of the compounds of the invention can be prepared from racemates by resolution using methods known in the art for the separation of racemic mixtures into their constituent stereoisomers, for example, using HPLC on a chiral column, such as Hypersil naphthyl urea, or using separation of salts of stereoisomers.
  • Compounds of the invention can be isolated in asso- ciation with solvent molecules by crystallization from, or evaporation of, an appropriate solvent.
  • the pharmaceutically acceptable acid addition salts of the compounds of formula (I) that contain a basic center can be prepared in a convention- al manner.
  • a solution of the free base can be treated with a suitable acid, either neat or in a suitable solution, and the resulting salt isolated either by filtration or by evaporation under vacuum of the reaction solvent.
  • Pharmaceutically acceptable base addition salts can be obtained in an analogous manner by treating a solution of a compound of formula (I) with a suitable base. Both types of salt can be formed or interconverted using ion-exchange resin techniques.
  • a method for preparing a compound of formula (I) or a salt or sol- vate is provided, followed by (i) salt formation, or (ii) solvate (e.g., hydrate) formation.
  • salt formation or solvate (e.g., hydrate) formation.
  • solvate e.g., hydrate
  • Example 1 can be prepared using the following synthetic sequence.
  • Example 1 can be prepared using the following synthetic sequence.
  • Example 1 was prepared by the following alternative method. A suspension of Intermediate 1
  • Example 1 (silica gel, 30% ethyl acetate: 70% hexanes) to provide 602 mg (55%) of Example 1 as a solid. mp 197-202°C.
  • E NMR (DMSO-d s ) ⁇ : 10.7 (s, IH) , 7.55- 6.35 (m, 7H) , 6.0 (d, J 15 Hz, 2H) , 5.8 (s, IH) , 4.9
  • Example 2 was prepared using the following synthetic sequence.
  • Example 3 was prepared by the following synthetic schemes.
  • Triethylamine (0.39 mL, 2.98 mmol) was added to a stirred mixture of Intermediate 1 (1 g, 2.7 mmol) and thiocarbonyl diimidazole (0.57 g, 3.2 mmol) in CH 2 C1 2 (15 mL) at room temperature. The resulting slurry was stirred for 18 hours at room temperature. The resulting solution was concen- trated in vacuo . Chromatography (silica gel, hex- anes to 6:4 methylene chloride :hexanes) of the residue provided 0.33 g (32%) of Example 3 as a cream solid: 129-132°C.
  • Example 3 also can be prepared by the following synthetic sequence: thiophosgene
  • Example 4 is prepared from Example 1 by the following reaction.
  • Example 5 is prepared from Intermediate 5 via a reaction with Lawesson 's reagent. The synthesis of Intermediate 5 can be found in Daugan et al . U.S. Patent No. 6,001,847.
  • Lawesson ' s reagent (0.43 g, 1.07 mmol) was added to a slurry of Intermediate 5 (0.40 g, 1.07 mmol) in anhydrous THF (25 mL) . The mixture was stirred under a nitrogen blanket for 8 days at room temperature . LC/MS showed two peaks corresponding to Example 5, but only in 5-10% yield. The reaction mixture was concentrated in vacuo and was taken up in toluene. An additional 80 mg of Lawesson' s reagent was added and the slurry was warmed to 80 °C for 4 hours.
  • the reaction was cooled to room tem- perature, diluted with EtOAc (50 mL) , and washed with saturated NaCl solution (20 mL) .
  • the organic layer was dried over MgS0 4 , filtered, and concentrated in vacuo .
  • the product was purified by column chromatography (silica gel, 0-5%) EtOAc/CH 2 Cl 2 ) to provide an orange foam.
  • Example 5 The relative stereochemistry of Example 5 was confirmed to be the trans isomer by NOE difference experiments (DMSO-d 6 ) : no NOE en- hancements from the C12a proton at 4.90 ppm to the C6 proton at 6.17 ppm and a positive enhancement with a C12 proton at 3.56 ppm.
  • Example 6 Anal. Calcd for C 21 H 17 N 3 0 3 S : C, 64.43; H, 4.38; N, 10.73; S, 8.19. Found: C. 64.52; H, 4.49; N, 10.54; S,8.36.
  • the relative stereochemistry of Example 6 was confirmed to be the trans isomer by NOE difference experiments (DMS0-D 6 ) : no NOE enhancements from the C3a proton at 4.87 ppm to the CIO proton at 6.77 ppm and a positive enhancement with benzene protons at 6.89-7.05 ppm.
  • Example 6a was prepared in a manner identical to Example 6 using the appropriate stereo- isomer of ⁇ -carboline hydrochloride, i.e., Intermediate III.
  • Examples 7-16
  • Examples 7-16 were prepared in a manner similar to Examples l-6a.
  • a compound of formula (I) can be formed into a dispersion with a polymeric carrier by the coprecipitation method set forth in WO 96/38131, incorporated herein by reference.
  • the coprecipi- tated dispersion then can be blended with excipients, then pressed into tablets, which optionally are film-coated.
  • the compounds of structural formula (I) were tested for an ability to inhibit PDE5.
  • the ability of a compound to inhibit PDE5 activity is related to the IC 50 value for the compound, i.e., the concentration of inhibitor required for 50% inhibition of enzyme activity.
  • the IC 50 value for compounds of structural formula (I) were determined using recombinant human PDE5.
  • the compounds of the present invention typically exhibit an IC 50 value against recombinant human PDE5 of less than about 50 ⁇ M, and preferably less than about 25 ⁇ M, and more preferably less than about 15 ⁇ m.
  • the compounds of the present invention typically exhibit an IC 50 value against recombinant human PDE5 of less than about 1 ⁇ M, and often less than about 0.05 ⁇ M .
  • a present PDE5 inhibitor has an IC 50 of about 0.1 nM to about 15 ⁇ M .
  • yeast ADH2 promoter and terminator sequences were incorporated in yeast ADH2 promoter and terminator sequences and the Saccharomyces cerevisiae host was the protease-defi- cient strain BJ2-54 deposited on August 31, 1998 with the American Type Culture Collection, Manassas, Virginia, under accession number ATCC 74465. Transformed host cells were grown in 2X SC-leu medium, pH 6.2, with trace metals, and vitamins. After 24 hours, YEP medium-containing glycerol was added to a final concentration of 2X YET/3% glycerol. Approximately 24 hr later, cells were harvested, washed, and stored at -70 °C.
  • Phosphodiesterase activity of the prepara- tions was determined as follows. PDE assays utilizing a charcoal separation technique were performed essentially as described in Loughney et al . (1996) . In this assay, PDE activity converts [32P] cAMP or [32P]cGMP to the corresponding [32P] 5 ' -AMP or [32P]5'-GMP in proportion to the amount of PDE activity present. The [32P] 5 ' -AMP or [32P] 5 ' -GMP then was quantitatively converted to free [32P] phosphate and unlabeled adenosine or guanosine by the action of snake venom 5 ' -nucleotidase .
  • the amount of [32P] phosphate liberated is proportional to enzyme activity.
  • the assay was performed at 30°C in a 100 ⁇ l ⁇ reaction mixture containing (final concentrations) 40 mM Tris HCl (pH 8.0), 1 ⁇ M ZnS0 4 , 5 mM MgCl 2 , and 0.1 , mg/mL bovine serum albumin (BSA) .
  • PDE enzyme was present in quantities that yield ⁇ 30% total hydrolysis of substrate (linear assay conditions) .
  • the assay was initiated by addition of substrate (1 mM [32P] cAMP or cGMP) , and the mixture was incubated for 12 minutes.
  • Buffer A (20 mM Bis-Tris Propane, pH 6.8, 1 mM MgCl 2 , 0.25 mM DTT, 10 ⁇ M ZnSO and eluted with a step gradient of 125 mM NaCl in Buffer A followed by a linear gradient of 125-1000 mM NaCl in Buffer A.
  • Active fractions from the linear gradient were applied to a 180 mL hydroxyapatite column in Buffer B (20 mM Bis-Tris Propane (pH 6.8), 1 mM MgCl 2 , 0.25 mM DTT, 10 M ZnS0 4 , and 250 mM KC1) . After loading, the column was washed with 2 volumes of Buffer B and eluted with a linear gradient of 0-125 mM potassium phosphate in Buffer B.
  • Active fractions were pooled, precipitated with 60% ammonium sulfate, and resuspended in Buffer C (20 mM Bis-Tris Propane, pH 6.8, 125 M NaCl, 0.5 mM DTT, and 10 ⁇ M ZnS0 4 ) .
  • the pool was applied to a 140 mL column of ® SEPHACRYL S-300 HR and eluted with Buffer C. Active fractions were diluted to 50% glycerol and stored at -20°C.
  • the resultant preparations were about 85% pure by SDS-PAGE. These preparations had specific activities of about 3 jumol cGMP hydrolyzed per minute per milligram protein.
  • cGMP-PDE activity of compounds of the present invention was measured using a one-step assay adapted from Wells et al . , Biochim. Biophys . Acta, 384, 430 (1975) .
  • the reaction medium contained 50 mM Tris-HCl, pH 7.5, 5 mM magnesium ace- tate, 250 ⁇ g/ml 5 ' -Nucleotidase, 1 mM EGTA, and 0.15 ⁇ M 8-[H 3 ]-cGMP.
  • the enzyme used was a human recombinant PDE5 (ICOS Corp., Bothell, Washington).

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Abstract

Cette invention, qui a trait à des composés correspondant à la formule générale de structure (I), concerne également l'utilisation de ces composés, de leurs sels et de leurs solvates en tant qu'agents thérapeutiques.
PCT/US2001/042175 2000-10-03 2001-09-17 Composés chimiques WO2002028865A2 (fr)

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DE60121461T DE60121461T2 (de) 2000-10-03 2001-09-17 Kondensierte pyridoindolderivate
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US10/363,528 US6858620B2 (en) 2000-10-03 2001-09-17 Condensed pyridoindole derivatives
MXPA03002911A MXPA03002911A (es) 2000-10-03 2001-09-17 Compuestos quimicos.
AU2002213421A AU2002213421A1 (en) 2000-10-03 2001-09-17 Condensed pyridoindole derivatives
CA002423312A CA2423312A1 (fr) 2000-10-03 2001-09-17 Composes chimiques
EP01981804A EP1335923B1 (fr) 2000-10-03 2001-09-17 Derives condenses du pyridoindole

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WO2006079644A1 (fr) * 2005-01-28 2006-08-03 Nycomed Gmbh Indolopyridines, benzofuranopyridines et benzothienopyridines
WO2008125658A1 (fr) * 2007-04-13 2008-10-23 Fourtillan Derives de 4,5,11,11a-tetrahydro-1h,6h-oxazolo[3',4':1,6]pyrido[3,4-b]indol-3-one et leur utilisation en therapeutique
US7718665B2 (en) 2004-08-18 2010-05-18 4Sc Ag Benzothienopyridines for use as inhibitors of Eg5 kinesin
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US20120283282A1 (en) * 2009-06-18 2012-11-08 Arleen Rifkind Photoproducts of Tryptophan, Their Synthesis and Uses Thereof
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EP2196201A2 (fr) 2002-12-13 2010-06-16 Warner-Lambert Company LLC Combinaison d'un ligand alpha-2-delta avec un inhibiteur de pdev ou avec un antagoniste muscarinique pour traiter les symptomes des voies urinaires inferieures
WO2005089752A3 (fr) * 2004-03-15 2005-12-15 Ptc Therapeutics Inc Derives de carboline tetra-cyclique utiles pour inhiber l'angiogenese
JP2007529533A (ja) * 2004-03-15 2007-10-25 ピーティーシー セラピューティクス，インコーポレーテッド 血管新生の抑制に有用なテトラサイクリックカルボリン誘導体
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WO2006079645A1 (fr) * 2005-01-27 2006-08-03 Nycomed Gmbh Nouvelles indolopyridines, benzofuranopyridines et benzothienopyridines
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WO2002028865A3 (fr) 2003-02-27
EP1335923A2 (fr) 2003-08-20
EP1335923B1 (fr) 2006-07-12
DE60121461T2 (de) 2007-02-08
AU2002213421A1 (en) 2002-04-15
US20040082787A1 (en) 2004-04-29
ATE332903T1 (de) 2006-08-15
JP4246488B2 (ja) 2009-04-02
JP2004511448A (ja) 2004-04-15
US6858620B2 (en) 2005-02-22
ES2267831T3 (es) 2007-03-16
MXPA03002911A (es) 2003-09-10
DE60121461D1 (de) 2006-08-24
CA2423312A1 (fr) 2002-04-11

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